Project Summary/Abstract In sub-Saharan Africa, the scale-up of antiretroviral (ARV) prophylaxis for the prevention of mother-to-child HIV transmission, as well as improved understanding of risk factors for transmission through breastfeeding, have dramatically reduced the number of infants becoming infected resulting in the number of HIV-exposed, uninfected (HIV-EU) children being born rising to dwarf even the staggering number of children infected with HIV. Under appreciated is a growing body of data that these HIV- EU are at risk for early life development abnormalities including growth faltering, higher morbidities, and increased risk for infant diarrhea during the first two years of life compared to children born to HIV-uninfected mothers (HIV-unexposed, HIV-UU). We hypothesize that the infant's altered gut microbiota: 1) is inherited from the mother; 2) persists over the critical early age of development; and 3) contributes to the reported growth abnormalities and adverse clinical outcomes for the infant. The investigative team, led by the University of Maryland School of Medicine's Institute of Human Virology and Institute for Genome Sciences proposes the Microbiome Affects Risk of Growth in HIV-exposed but Uninfected Infants in Nigeria (MARGIN) Study. MARGIN addresses scientific knowledge gaps in the critical window of time for growth and health of HIV-EU compared to HIV-UU through these innovative specific aims: (1) Characterize the relationship of infants' early gut microbiota to maternal pattern; (2) Characterize the functional differences in the infant gut microbiota between HIV-EU and HIV-UU infants; (3) Determine the associations between clinical outcomes and the structure and function of the infants' gut microbiota. This innovative strategy for understanding the role of the microbiome in growth and development not only has implications for addressing the significant public health challenge impacting 15% of all newborn babies in sub-Saharan Africa but also provides fundamental biological insight into the interface between host and microbiota and the role of the mother in the evolution of infant microbiota. From a translational perspective, this study lays the foundation for developing science-driven interventions such as probiotics to restore a favorable gut microbiota and its integrity, support growth, and mitigate persistent diarrhea and other recurrent infections among HIV-EU.